Austin Clin Neurol 2014;1(1): 1001.
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston
*Corresponding author: Hirohide Asai, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Laboratory of Molecular NeuroTherapeutics, 72 East Concord Street, Boston, MA
Received: January 08, 2014; Accepted: January 15, 2014; Published: January 17, 2014
A subset of infiltrating peripheral monocytes is known to be recruited to CNS by monocyte chemoattractant protein–1 (MCP–1⁄ CCL2) signaling in various neurological diseases. We have recently reported striking switch in the activation phenotype and population of mononuclear phagocytes from resident microglia to infiltrating macrophages in neuronal cell death induced CCL2 dependent manner in a mouse model which overexpressed Tau–Tubulin Kinase–1 (TTBK1) .Although TTBK1 up regulation is detected in brains of human Alzheimer’s disease (AD), this dramatic conversion of the cell population from microglia to pro–inflammatory M1– skewed infiltrating monocytes are well characterized in the patients with acute stroke. In this short communication, I introduce the role of CCL2 in macrophage filtration to affected region of the acute is chemic stroke and AD brain.
In our TTBK1 overexpression mice, danger–associated molecular pattern molecules (DAMPs, such as ATP, DNA, S100, and chromatinassociated molecules released from injured neurons) activate proinflammatory M1–like innate immunity response of mononuclear phagocytes and CCL2 production. This leads to the recruitment of peripheral macrophages into the affected brain region and acceleration of neuronal cell death via bystander killing of neurons. Infiltrating macrophages are known to serve as a key mediator of the innate immune response by their expression of Toll–like receptors (TLRs) and activation of TLRs of macrophages leads to the secretion of pro–inflammatory cytokines. In post–ischemic inflammation, the central event is also recruitment of leukocytes, first neutrophils, and then an influx of cells of the monocyte⁄macrophage lineage. Experimentally, CCL2 overexpression increases the infarct volume and monocytes and macrophages invasion of the ischemic area . In contrast, CCL2–deficient mice are resistant to permanent middle cerebral artery occlusion  and the expression by gene transfer of dominant negative CCL2 in the post–ischemic period in hypertensive rats reduced the infarct volume and leukocyte infiltration . In the human AD brain, increased expression of pro–inflammatory cytokines or chemokines is accompanied by M1–skewed microglial activation. Additionally, CCL2 levels are known to be associated with cognitive decline during the early stage of AD patients [5–8]. These findings are reproduced in several AD mouse models such as the APP+PS1 mouse , which shows a distinctive age–dependent shift from M2 (anti–inflammatory) to M1 (pro–inflammatory) mononuclear cell activation in the hippocampus.
Taken together, CCL2 and its receptor CCR2 should be important targets in the development of treatments to fight or prevent acute and chronic neurological disorders in which neuroinflammation is a pathological key event.
- Asai H, Ikezu S, Woodbury ME, Yonemoto GM, Cui L, Ikezu T. Accelerated neurodegeneration and neuroinlammation in transgenic mice expressing P301L tau mutant and tau-tubulin kinase 1. Am J Pathol. 2014; 184: 808-818.
- Chen Y, Hallenbeck JM, Ruetzler C, Bol D, Thomas K, Berman NE, et al. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inlammatory cells. J Cereb Blood Flow Metab. 2003; 23: 748-755.
- Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK. Monocyte chemoattractant protein-1 deiciency is protective in a murine stroke model. J Cereb Blood Flow Metab. 2002; 22: 308-317.
- Kumai Y, Ooboshi H, Takada J, Kamouchi M, Kitazono T, Egashira K, et al. Anti-monocyte chemoattractant protein-1 gene therapy protects against focal brain ischemia in hypertensive rats. J Cereb Blood Flow Metab. 2004; 24: 1359-1368.
- Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S. CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS One. 2012; 7: 30525.
- Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inlammation observed in Alzheimer’s disease. Brain Pathol. 2009; 19: 392-398.
- Galimberti D, Schoonenboom N, Scarpini E, Scheltens P, Dutch-Italian Alzheimer Research Group. Chemokines in serum and cerebrospinal luid of Alzheimer’s disease patients. Ann Neurol. 2003; 53: 547-548.
- Jankowsky JL, Slunt HH, Gonzales V, Jenkins NA, Copeland NG. APP processing and amyloid deposition in mice haplo-insuficient for presenilin 1. Neurobiol Aging. 2004; 25: 885-892.
- Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M Sanchez-Varo R, et al. Inlammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent